Substituted piperazine-1,4-naphthalenediones useful as anti-asthmatic agents

ABSTRACT

This disclosure describes certain substituted piperazine-1,4-naphthalenediones useful as anti-asthmatic agents.

CROSS REFERENCE TO RELATED APPLICATION

This application is a division of our copending application Ser. No.046,365, filed May 6, 1987, now U.S. Pat. No. 4,771,061 which is adivision of our application Ser. No. 811,122, filed Dec. 19, 1985, nowU.S. Pat. No. 4,686,220.

SUMMARY OF THE INVENTION

This invention is concerned with new compounds selected from those ofthe formula: ##STR1## wherein R₁ is selected from the group consistingof halogen, hydroxy, alkyl(C₁ -C₄), alkoxy(C₁ -C₃), --NHCOCH₃ and--N(COCH₃)₂ ; R₂ is selected from the group consisting of hydrogen andalkyl(C₁ -C₄); R₃ and R₄ are individually alkyl(C₁ -C₃), or when takentogether are --(CH₂)_(n) --, where n is an integer 2 or 3; R₅ isselected from the group consisting of hydrogen, formyl, acetyl,--COOalkyl(C₁ -C₄), --COOCH₂ C--(halogen)₃, --CO(CH₂)₇ CH═CH(CH₂)₇ CH₃,--CON[alkyl(C₁ -C₃)]₂, phenyl, benzyl, 2-, 3- or 4-pyridinyl,2-pyrimidinyl, 2-, 3- or 4-halobenzoyl, 2-, 3- or 4-alkyl(C₁ 14C₆)benzoyl, monosubstituted phenyl (wherein the substituents may beortho, meta or para and are selected from the group consisting ofhalogen and trifluoromethyl), monosubstituted phenyl carboxamide(wherein the substitutents may be meta and para and are selected fromthe group consisting of halogen and trifluoromethyl), ##STR2## thepharmacologically acceptable acid-addition salts thereof.

In addition this invention is concerned with a method of treating asthmaand allergic diseases and inflammation in warm-blooded animals and withcompositions of matter employing the above compounds.

Further, this invention is concerned with processes of producing theabove compounds.

DESCRIPTION OF THE INVENTION

The compounds of this invention may be prepared by the followingmethods:

FLOWCHART I ##STR3##

According to Flowchart I, 2, 3-dichloronaphthoquinone 1, is reacted withan amine 2, where R₂, R₃, R₄ and R₅ are as described above, in absoluteethanol at reflux for several hours producing the3-chloro-1,4-napththalenedione derivatives 3.

FLOWCHART II ##STR4##

According to Flowchart II, substituting2-acetylamino-3-chloro-1,4-naphthoquinone 4 in the reaction describedfor Flowchart I produces the 3-acetylamino-1,4-naphthalenedionederivatives 5.

FLOWCHART III ##STR5##

According to Flowchart III, a3-chloro-2-substituted-1,4-naphthalenedione 6, where R₂, R₃ and R₄ areas described above is reacted with a substituted phenyl isocyanate 7,where X is halogen or trifluoromethyl in an organic solvent such aschloroform or ether for several hours, producing the3-chloro-1-piperazinecarboxamide derivatives 8.

FLOWCHART IV ##STR6##

According to Flowchart IV, a 3-chloro-2-substituted-1,4-naphthalenedione6, where R₂, R₃ and R₄ are as described above is reacted with a carbonylchloride 9, where Y may be O-alkyl(C₁ -C₆), dimethylamino, substitutedphenyl [wherein the substituents may be halogen or alkyl-(C₁ -C₄)],O-benzyl, --OCH₂ C(halogen)₃ or --(CH₂)₇ CH═CH(CH₂)₇ CH₃ intetrahydrofuran producing the 3-chloro-1,4-naphthalenedione carboxylicacid derivatives 10.

FLOWCHART V ##STR7##

According to Flowchart V, 2,3-epoxy-2-methyl-1,4-naphthoquinone 11 isreacted with an amine 2, where R₂, R₃, R₄ and R₅ are as described above,in absolute ethanol with heat for several hours, producing the3-methyl-1,4-naphthalenedione derivatives 12.

3-Hydroxy analogs may be produced by substituting2,3-epoxy-2,3-dihydro-1,4-naphthoquinone in the reaction scheme forFlowchart V.

The novel compounds of the present invention are highly active asantiasthmatic and antiallergic agents as will be demonstratedhereinbelow.

The bronchospasm of allergic asthma is a consequence of the release ofmediators, such as histamine and slow-reacting substances from mastcells. The role of mediator release in the induction of an asthmaticattack has been fully reviewed and documented, see Kaliner, M. andAusten, K. F., Bronchial Asthma Mechanisms and Therapeutics, E. B.Weiss, Editor, Little, Brown and Company, Boston, 163 (1976);Lichtenstein, L. M., Asthmaphysiology, Immunopharmacology and Treatment,Second International Symposium, L. M. Lichtenstein and K. F. Austen,Editors, Academic Press, New York, 51 (1979); and Bell, S. C., et al.,Annual Reports in Medicinal Chemistry, 14, 51, H. J. Hess, Editor,Academic Press, New York (1979).

The novel compounds of this invention have been tested by the procedureof Lichtenstein, L. M. and Osler, A. G., J. Exp. Med., 120, 507-530(1964), which evaluates the ability of compounds to inhibit mediator(histamine) release from immunologically stimulated human basophils.

Reagents

10X Concentrated Tris Buffer

Dissolve 140.3 g of sodium chloride, 7.45 g of potassium chloride and74.5 g of Trizma-Tris Pre-Set, Reagent Grade, pH 7.6, at 25° C. (SigmaChemical Co.) in sufficient water to give a final volume of 2 liters.

Human Albumin

(Sigma Chemical Co.) (30 mg/ml)

Calcium and Magnesium Stocks

Made to 0.075M and 0.5M respectively, with calcium chloride dihydrateand magnesium chloride hexahydrate.

Tris-A Buffer

A 10 ml portion of 10X Tris Buffer and 1.0 ml of human albumin arediluted to 100 ml with water.

Tris ACM Buffer

A 10 ml portion of 10X Tris Buffer, 1.0 ml of human albumin, 0.8 ml ofcalcium stock and 0.2 ml of magnesium stock are diluted to 100 ml withwater.

Rabbit Antihuman IgE

Behring Diagnostics (Generally used at 10 μg protein/ml finalconcentration.)

House Dust Mite Extract (Dermatophagoides Farinae)

Strength 1:100 (w:v) allergenic extract, Hollister-Stier Labs. Generallythis is diluted 1:1000 to 1:10,000 (considering the vial as stock).

Other Allergens

Intradermal solutions or intramuscular preparations forhyposensitization, Hollister-Stier Labs. The final concentration used ison the order of 1 PNU/ml.

Separation of Leukocytes from Human Blood and Challenge

Eighty milliliters of blood is withdrawn from subjects with knownhistamine release to anti-IgE, ragweed antigen or other specificallergen, using four 20 ml heparinized tubes. This 80 ml of blood ismixed with 20 ml of saline containing 0.6 g of dextrose and 1.2 g ofdextran. The blood is allowed to sediment at room temperature in two 50ml polycarbonate centrifuge tubes until a sharp interface developsbetween the red cells and plasma (60-90 minutes). The plasma (top) layerfrom each tube is withdrawn by pipet and transferred to respective 50 mlpolycarbonate tubes. The plasma is centrifuged for 8 minutes at 110×G at4° C. The supernatant is carefully poured off as completely as possibleand the cell button is resuspended in 2-3 ml of Tris-A buffer using asiliconized Pasteur pipet. The resuspension is accomplished by drawingthe liquid gently in an out of the pipet, with the tip below the liquid,until an even suspension of cells is obtained. Sufficient Tris-A bufferis then added to bring the volume in the tube to about 45 ml and thetube is centrifuged at 110×G for 8 minutes at 4° C. The supernatant ispoured off and the cell button is resuspended and centrifuged asdescribed above. The supernatant is poured off and the cell buttonsuspended in 2-3 ml of Tris-ACM buffer to make the final volumesufficient to allow addition to the reaction tubes.

Reaction tubes containing anti-IgE or antigens, either alone or withtest compound in a total volume of 0.2 ml are prepared and placed in a37° C. bath. The cells are warmed to 37° C. and frequently swirled toensure an even suspension, while 1.0 ml aliquots are added to eachreaction tube. The tubes are then incubated for 60 minutes at 37 ° C.,vortexing the tubes gently every 15 minutes to keep the cells evenlysuspended. When the reaction is complete, the tubes are centrifuged at4° C. for 10 minutes at 1500 rpm to sediment the cells. One ml aliquotsof supernatant are transferred to 12 mm by 75 mm polyethylene tubes and0.2 ml of 8% perchloric acid is added to each tube. Blanks and totalsare included in each test. The blanks have cells and all reagents exceptantigen or anti-IgE. The totals contain 0.24 ml of 8% perchloric acid,one ml of cells and 0.2 ml of buffer. All samples are then centrifugedto remove the precipitate protein.

Assay of Released Histamine by the Automated Fluorometric Method

This automated method has been described by Siraganian, R. P., in Anal.Biochem., 57, 383 (1974) and J. Immunol. Methods, 7, 283 (1975) and isbased on the manual method of Shore, P. A., et al., J. Pharmacol. Exp.Ther., 217, 182 (1959).

The automated system consists of the following Technicon Autoanalyzer IIcomponents: Sampler IV, Dual-Speed Proportioning Pump III,Fluoronephelometer with a narrow pass primary filter 7-60 and asecondary filter 3-74, Recorder, and Digital Printer. The manifold usedis the one described by Siraganian vide supra, with the followingmodifications: the dialyzer is omitted; all pumping tubes pass through asingle proportioning pump with large capacity and twice the volume ofsample is taken for analysis.

The automated chemistry consists of the following steps: Extraction fromalkaline saline into butanol, back extraction into dilute hydrochloricacid by addition of heptane, reaction of histamine witho-phthaldialdehyde (OPT) at high pH and conversion of the OPT adduct toa stable fluorophore with phosphoric acid. The reaction product is thenpassed through the fluorometer. The full scale response is adjusted to50 ng histamine base with a threshold sensitivity of approximately 0.5ng.

Calculation of the Results of Histamine Release Tests

The instrument blank (wash) is substracted from the ng histamine of eachsample. Then the ng histamine of each sample is divided by the mean ofthe three totals (cells lysed with perchloric acid) to obtain percentrelease.

Control samples contain antigen but no test compound. Blank (orspontaneous release) samples contain neither antigen nor test compound.The mean of the blanks (three replicates) is substracted from thepercent release for controls and test compounds.

The means for control and test compound groups are computed and theresult for a test compound is computed as percent of control by theformula:

    100×% Histamine Release with Test compound/ % Histamine Release in Controls

Values obtained at different concentrations of test compound are used tocalculate an ED₅₀ (the concentration in μM which causes a 50% inhibitionof histamine release) by linear regression. A compound is consideredactive if the ED₅₀ is ≦48 μM.

The results of this test on typical compounds of this invention appearin Table I.

                  TABLE I                                                         ______________________________________                                        Inhibition of Histamine Release from Immunologically                          Stimulated Human Basophils                                                    Compound                   ED.sub.50 μM                                    ______________________________________                                        4-(3-chloro-1,4-dioxo-2-naphthyl)-1-piperazine-                                                          5.5                                                carboxylic acid, ethyl ester                                                  2-chloro-3-[methyl[2-[methyl(phenylmethyl)amino]-                                                        4.0                                                ethyl]amino]-1,4-naphthalenedione, hydrochloride                              2-chloro-3-[4-(phenylmethyl)-1-piperazinyl]-1,4-                                                         10.4                                               naphthalenedione                                                              4-[[4-(3-chloro-1,4-dihydro-1,4-dioxo-2-naphtha-                                                         20.6                                               lenyl)-1-piperazinyl]acetyl]morpholine                                        1-[[4-(3-chloro-1,4-dihydro-1,4-dioxo-2-naphtha-                                                         14.9                                               lenyl)-1-piperazinyl]acetyl]pyrrolidine                                       2-chloro-3-[4-(2-pyridinyl)-1-piperazinyl]-1,4-                                                          4.6                                                naphthalenedione, hydrochloride                                               2-[[2-(2-benzothiazolylmethylamino)ethyl]methyl-                                                         6.4                                                amino]-3-chloro-1,4-naphthalenedione                                          2-chloro-3-[4-(phenylmethyl)-1-piperazinyl]-1,4-                                                         13.4                                               naphthalenedione, hydrochloride                                               2-[4-(2-benzothiazolyl)-1-piperazinyl]-3-chloro-                                                         5.4                                                1,4-naphthalenedione, hydrochloride                                           4-(3-chloro-1,4-dihydro-1,4-dioxo-2-naphtha-                                                             1.5                                                lenyl)-1-piperazinecarboxylic acid, ethyl ester,                              hydrochloride                                                                 2-chloro-3-(3-methyl-1-piperazinyl)-1,4-naphtha-                                                         3.0                                                lenedione                                                                     4-(3-chloro-1,4-dihydro-1,4-dioxo-2-naphtha-                                                             16.5                                               lenyl)-1-piperazinecarboxylic acid, 2-methyl-                                 propyl ester                                                                  1-(2-chlorobenzoyl)-4-(3-chloro-1,4-dihydro-                                                             1.8                                                1,4-dioxo-2-naphthalenyl)piperazine                                           ______________________________________                                    

The ability of these compounds to inhibit lipoxygenase activity in termsof the suppression of the release and biosynthesis of leukotriene B4(LTB4) and 5-hydroxy-eicosatetraenoic acid (5-HETE) was measured asfollows.

In this assay 3×10⁷ peritoneal neutrophils derived from guinea pigs wereincubated at 37° C. in Dulbeccos buffer containing 50 mM tris buffer (pH7.4). Five minutes before the addition of 100 μM arachidonic acid and 20μM calcium ionophore (A23187), control vehicle or the test compoundswere added to the neutrophils at a concentration of 10 μg/ml.

Three minutes after the addition of arachidonic acid and calciumionophore the total lipid was partitioned into chloroform afteradjusting the pH to 3 with citric acid and the addition of equal partsof methanol and chloroform.

The 5-HETE and LTB4 were resolved by HPLC using a 5 μM, 4×25 cmoctadecyl silica column (IBM Instruments) with 70-80% methanol in wateradjusted to pH 3.0 with acetic acid. As the mobile phase was pumped at1.0 ml/-minute, LTB4 and 5-HETE were detected by absorbance at 270 and236 nm, respectively.

LTB4 and 5-HETE were quantitated by comparison with the control and theresults were expressed as a percent of control. The lower thepercentage, the more active the compound.

The results of this test on representative compounds of this inventionappear in Table II.

                  TABLE II                                                        ______________________________________                                        Inhibition of Neutrophil Lipoxygenase from                                    Immunologically Stimulated Guinea Pig Neutrophiles                                                  % of Control                                            Compound                LTB4    5-HETE                                        ______________________________________                                        4-(3-chloro-1,4-dioxo-2-naphthyl)-1-pipera-                                                           0       0                                             zinecarboxylic acid, ethyl ester                                              2-chloro-3-[4-(phenylmethyl)-1-pipera-                                                                0       0                                             zinyl]-1,4-naphthalenedione                                                   2-chloro-3-[4-(2-quinolinyl)-1-piperazin-                                                             0       0                                             yl]-1,4-naphthalenedione, hydrochloride                                       4-(3-chloro-1,4-dihydro-1,4-dioxo-2-naph-                                                             22.2    19.9                                          thalenyl) .sub.--N--(2-chlorophenyl)-1-piperazine-                            carboxamide                                                                   4-(3-chloro-1,4-dihydro-1,4-dioxo-2-naph-                                                             0       2.0                                           thalenyl)- .sub.--N--(2-fluorophenyl)-1-piperazine-                           carboxamide                                                                   2-[4-(1,3-benzodioxol-5-ylmethyl)-1-pipera-                                                           0       0                                             zinyl]-3-chloro-1,4-naphthalenedione,                                         hydrochloride                                                                 4-(3-chloro-1,4-dihydro-1,4-dioxo-2-naph-                                                             --*     0                                             thalenyl)- .sub.--N--[3-(trifluoromethyl)phenyl]-                             1-piperazinecarboxamide                                                        .sub.--N--[3-[4-(2-benzothiazolyl)-1-piperazinyl]-                                                   0       0                                             1,4-dihydro-1,4-dioxo-2-naphthalenyl]-                                        acetamide                                                                     4-(3-chloro-1,4-dihydro-1,4-dioxo-2-naph-                                                             --      1.4                                           thalenyl)- .sub.--N--(4-chlorophenyl)-1-piperazine-                           carboxamide                                                                   2-chloro-3-[4-(2-pyridinyl)-1-piperazinyl]-                                                           6.1     1.3                                           1,4-naphthalenedione, hydrochloride                                           2-[[2-(2-benzothiazolylmethylamino)ethyl]-                                                            0       0.2                                           methylamino]-3-chloro-1,4-napthalenedione                                     2-[4-(2-benzothiazolyl)hexahydro-1 .sub.--H-1,4-                                                      --      1.1                                           diazepin-1-yl]-3-chloro-1,4-naphthalene-                                      dione                                                                         2-chloro-3-[4-(2-pyrimidinyl)-1-piperazin-                                                            --      34.3                                          yl]-1,4-naphthalenedione                                                      4-(1,4-dihydro-3-methyl-1,4-dioxo-2-naph-                                                             --      2.2                                           thalenyl)-1-piperazinecarboxylic acid,                                        ethyl ester                                                                   2-[4-(2-benzothiazolyl)-1-piperazinyl]-3-                                                             20.8    0.8                                           methyl-1,4-naphthalenedione                                                   2-methyl-3-[4-(phenylmethyl)-1-piperazin-                                                             4.8     0.7                                           yl]-1,4-naphthalenedione                                                      2-methyl-3-[4-[3-(trifluoromethyl)phenyl]-                                                            --      0                                             1-piperazinyl]-1,4-naphthalenedione                                            .sub.--N--[1,4-dihydro-1,4-dioxo-3-[4-[3-(tri-                                                       --      0.3                                           fluoromethyl)phenyl]-1-piperazinyl]-2-                                        naphthalenyl]acetamide                                                        2-methyl-3-[4-(2-pyridinyl)-1-piperazinyl]-                                                           0       0                                             1,4-naphthalenedione                                                           .sub.--N--(4-chlorophenyl)-4-(1,4-dihydro-3-mehyl-                                                   --      8.8                                           1,4-dioxo-2-naphthalenyl)-1-piperazine-                                       carboxamide                                                                   2-[4-(2-benzoxazolyl)-1-piperazinyl]-3-                                                               13.5    19.6                                          chloro-1,4-naphthalenedione                                                   2-chloro-3-[4-(phenylmethyl)-1-piperazin-                                                             28.3    35.6                                          yl]-1,4-naphthalenedione, hydrochloride                                       2-[4-(2-benzothiazolyl)-1-piperazinyl]-3-                                                             32.6    23.1                                          chloro-1,4-naphthalenedione, hydrochloride                                    4-(3-chloro-1,4-dihydro-1,4-dioxo-2-naph-                                                             9.3     6.9                                           thalenyl)-1-piperazinecarboxylic acid,                                        ethyl ester, hydrochloride                                                    4-(3-chloro-1,4-dihydro-1,4-dioxo-2-naph-                                                             15.2    25.7                                          thalenyl)-N--(3-chlorophenyl)-2-methyl-1-                                     piperazinecarboxamide                                                         4-(3-chloro-1,4-dihydro-1,4-dioxo-2-naph-                                                             27.4    31.6                                          thalenyl)-1-piperazinecarboxylic acid,                                        2-methylpropyl ester                                                          1-(4-butylbenzoyl)-4-(3-chloro-1,4-dihydro-                                                           23.2    13.7                                          1,4-dioxo-2-naphthalenyl)piperazine                                           ______________________________________                                         *Dashes in the LTB4 column represent no measurement because of assay          interference.                                                            

An in vivo test used to establish anti-asthma activity for the compoundsof the present invention is the mouse passive cutaneous anaphylaxis(PCA) test described as follows.

Preparation of Immunoglobulin E (IGE) and G (IGG)

Female B₆ XD₂ Fl mice (Jackson Laboratories) are given anintraperitoneal injection of 0.5 ml of saline with 1 mcg ofDNP-ovalbumin and 1 mg of aluminum hydroxide gel (Wyeth Amphojel®). Oneand two months later the mice are boosted with the same antigenpreparation. One week after the second boost the mice are sacrificed andthe serum collected. The sera are pooled and titered to obtain a 48 hourPCA lesion slightly greater than 1 cm in diameter.

Passive Cutaneous Anaphylaxis Test

At -50 hours (relative to antigen challenge at 0 time) 50 microliters ofIGE or IGG is injected intradermally on the side of the mouse posteriorto the axilla at the level of the diaphragm. At this point the mice areplaced in individual numbered cages and randomly assigned to controland/or treatment groups (typically 15 mice in the control group with 10in each treatment group). Challenge and reading are performed in serialorder so that reading of the assay is essentially blind. At -1 hour thecontrol animals receive an IP injection of 0.5 ml of a 0.05% solution ofcarboxymethylcellulose in saline. For drug treated animals the drug isdissolved or suspended in a 0.1% carboxymethylcellulose solution (totalvolume 0.5 ml) and administered orally at -1 hour. At 0 time the miceare anesthetized with ether and 0.5 ml of saline containing 0.1 mg ofdinitrophenylated (DNP)-ovalbumin and 2.5 mg Evans blue dye is injectedinto the tail vein. At +15 minutes the mice are sacrificed by cervicaldislocation, the dorsal skin removed, and the blue PCA spots areexamined on the inside surface. The largest and smallest diameters ofthe lesion and a qualitative estimate of intensity of color arerecorded. The mean of the products of diameters (area) for mice in agiven treatment group are compared with the control group. If the areafor a treatment group is significantly smaller than the lesion area forthe control group (p <0.05 for two-tailed student's t-test) the testcompound is considered active as an anti-asthmatic agent. Results fortypical compounds of this invention when tested as described aboveappear in Table III, wherein the inhibitory dose (ID₅₀) estimated toinhibit the size of lesions in 50% of the animals relative to control isgiven.

                  TABLE III                                                       ______________________________________                                        Mouse Passive Cutaneous Anaphylaxis Test                                                             ID.sub.50 μM                                        Compound                 IGE     IGG                                          ______________________________________                                        4-(3-chloro-1,4-dioxo-2-naphthyl)-1-pipera-                                                            61.0    16.0                                         zinecarboxylic acid, ethyl ester                                              2-chloro-3-[methyl[2-methyl(phenylmethyl)-                                                             30.3    41.2                                         amino]ethyl[amino]-1,4-naphthalenedione,                                      hydrochloride                                                                 2-chloro-3-[4-(phenylmethyl)-1-piperazinyl]-                                                           25.0    50.0                                         1,4-naphthalenedione                                                          1-[[4-(3-chloro-1,4-dihydro-1,4-dioxo-2-                                                               25.0    25.0                                         naphthalenyl)-1-piperazinyl]acetyl]pyrrolidine                                4-(3-chloro-1,4-dihydro-1,4-dioxo-2-naphtha-                                                           25.0    25.0                                         lenyl)-1-piperazinecarboxylic acid, ethyl                                     ester, hydrochloride                                                          ______________________________________                                    

The novel compounds of the present invention are effective asantiasthmatic agents in mammals when administered in amounts rangingfrom about 0.1 mg to about 100 mg/kg of body weight per day. A preferreddosage regimen for optimum results would be from about 0.1 mg to about25 mg/kg of body weight per day, and such dosage units are employed thata total of from about 7 mg to about 1.8 g of the active compound for asubject of about 70 kg of body weight are administered in a 24 hourperiod. This dosage regimen may be adjusted to provide the optimumthereapeutic response. For example, several divided doses may beadministered daily or the dose may be proportionally reduced asindicated by the exigencies of the therapeutic situation. A decidedpractical advantage is that these active compounds may be administeredin any convenient manner such as by the oral, aerosol, intravenous,intramuscular, or subcutaneous routes.

The active compounds may be orally administered, for example, with aninert diluent or with an assimilable edible carrier, or they may beenclosed in hard or soft shell gelatin capsules, or they may becompressed into tablets, or they may be incorporated directly with thefood of the diet. For oral therapeutic administration, these activecompounds may be incorporated with excipients and used in the form ofingestible tablets, buccal tablets, troches, capsules, elixirs,suspensions, syrups, wafers, suppositories and the like. Suchcompositions and preparations should contain at least 0.1% of activecompound. The percentage of the compositions and preparations may, ofcourse, be varied and may conveniently be between about 2% to about 60%of the weight of the unit. The amount of active compound in suchtherapeutically useful compositions is such that a suitable dosage willbe obtained. Preferred compositions or preparations according to thepresent invention are prepared so that an oral dosage unit form containsbetween about 5 and 200 mg of active compound.

The tablets, troches, pills, capsules and the like may also contain thefollowing: A binder such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, lactose or saccharin may be added or a flavoring agent such aspepermint, oil of wintergreen or cherry flavoring. When the dosage unitform is a capsule, it may contain, in addition to materials of the abovetype, a liquid carrier. Various other materials may be present ascoatings or to otherwise modify the physical form of the dosage unit.For instance, tablets, pills or capsules may be coated with shellac,sugar or both. A syrup or elixir may contain the active compound,sucrose as a sweetening agent, methyl and propylparabens aspreservatives, a dye and flavoring such as cherry or orange flavor. Ofcourse, any material used in preparing any dosage unit form should bepharmaceutically pure and substantially non-toxic in the amounts used.In addition, these active compounds may be incorporated intosustained-release preparations and formulations.

Compositions according to the present invention having the desiredclarity, stability and adaptability for parenteral use are obtained bydissolving from 0.10% to 10.0% by weight of active compound in a vehicleconsisting of a polyhydric aliphatic alcohol or mixtures thereof.Especially satisfactory are glycerin, propylene glycol, and polyethyleneglycols. The polyethylene glycols consist of a mixture of non-volatile,normally liquid, polyethylene glycols which are soluble in both waterand organic liquids and which have molecular weights of from about 200to 1500. Although various mixtures of the aforementioned non-volatilepolyethylene glycols may be employed, it is preferred to use a mixturehaving an average molecular weight of from about 200 to about 400.

In addition to the active compound, the parenteral solutions may containvarious preservatives which may be used to prevent bacterial and fungalcontamination. Such preservatives are, for example, myristyl-gammapicolinium chloride, phenyl mercuric nitrate, benzalkonium chloride,phenethyl alcohol, p-chlorophenyl-alpha-glycerol ether, methyl andpropyl parabens and thimerosal. As a practical matter, it is alsoconvenient to employ antioxidants. Suitable antioxidants include, forexample, sodium bisulfite, sodium metabisulfite and sodium formaldehydesulfoxylate. Generally, from about 0.05% to about 0.2% concentrations ofantioxidant are employed. These compounds may also be administered byinhalation using conventional Aerosol® formulations.

The invention will be described in greater detail in conjunction withthe following specific examples.

Example 1 4-(3-Chloro-1, 4-dioxo-2-naphthyl)-1-piperazinecarboxylicacid, ethyl ester

A mixture of 11.35 g of 2,3-dichloro-1,4-naohthoquinone, 15.8 g of1-piperazinecarboxylic acid, ethyl ester and 400 ml of absolute ethanolwas heated at reflux for 3 hours and then evaporated to dryness. Theresidue was taken up in 300 ml of dichloromethane and filtered throughsilica gel. The filtrate was evaporated and the residue triturated withether, giving 8.0 g of the desired product as red crystals, mp 120°-122°C.

Example 2 2-Chloro-3-[methyl[2-[methyl(phenylmethyl)amino]-ethyl]amino]-1,4-naphthalenedione, hydrochloride

A 4.5 g portion of methyl 2-[methyl (phenylmethyl)-amino]ethylamine wasadded to a stirred slurry of 5.6 g of 2,3-dichloro-1,4-naphthoquinone in150 ml of absolute ethanol. Stirring was continued for 16 hours, thenthe mixture was heated at reflux for one hour and filtered while hot.The mixture was then cooled at -10° C. and filtered. This filtrate wasdiluted with 100 ml of ether and cooled at -10° C. The resultingprecipitate was collected, washed with ether and dried in vacuo at 100°C., giving 3.5 g of the desired product as orange crystals, mp 188°-190°C. (dec.).

Following the procedure of Examples 1 and 2, using appropriate aminestarting materials and 2, 3-dichloro-1,4-naphthoquinone the products ofExamples 3-19, listed in Table IV were obtained.

                                      TABLE IV                                    __________________________________________________________________________    Ex.                                                                              Amine        Product                 MP °C.                         __________________________________________________________________________     3  .sub.--N--[3-(trifluoromethyl)-                                                           2-chloro-3-[4-[3-(trifluoromethyl)phenyl]-1-                                                          124-126                                  phenyl]piperazine                                                                          piperazinyl]-1,4-naphthalenedione                              4  .sub.--N--(p-chlorobenzhydryl)-                                                           2-chloro-3-[4-[(4-chlorophenyl)phenylmethyl]-1-                                                       158-161                                  piperazine   piperazinyl]-1,4-naphthalenedione                              5  .sub.--N--benzylpiperazine                                                                2-chloro-3-[4-(phenylmethyl)-1-piperazinyl]-1,4-                                                      oil                                                   naphthalenedione                                               6  .sub.--N--acetylmorpholino                                                                4-[[4-(3-chloro-1,4-dihydro-1,4-dioxo-2-naphtha-                                                      159-161                                  piperazine   lenyl)-1-piperazinyl]acetyl]morpholine                         7  .sub.--N--acetylpyrrolidino                                                               1-[[4-(3-chloro-1,4-dihydro-1,4-dioxo-2-naphtha-                                                      110-113                                  piperazine   lenyl)-1-piperazinyl]acetyl]pyrrolidine                        8  .sub.--N--(2-pyridinyl)piperazine                                                         2-chloro-3-[4-(2-pyridinyl)-1-piperazinyl]-1,4-                                                       oil                                                   naphthalenedione, hydrochloride                                9  .sub.--N--benzothiazolylmethyl-                                                           2-[[2-(2-benzothiazolylmethylamino)ethyl]methyl-                                                      oil                                      aminoethyl methylamine                                                                     amino]-3-chloro-1,4-naphthalenedione                          10  .sub.--N--(2-quinolinyl)pipera-                                                           2-chloro-3-[4-(2-quinolinyl)-1-piperazinyl]-1,4-                                                      >100                                     zine         naphthalenedione, hydrochloride                               11  .sub.--N--(1,3-benzodioxol-5-yl-                                                          2-[4-(1,3-benzodioxol-5-ylmethyl)-1-piperazinyl]-                                                     >200                                     methyl)piperazine                                                                          3-chloro-1,4-naphthalenedione, hydrochloride                  12  .sub.--N--(2-pyrimidinyl)pipera-                                                          2-chloro-3-[4-(2-pyrimidinyl)-1-piperazinyl]-1,4-                                                     136-137                                  zine         naphthalenedione                                              13 piperazinecarboxaldehyde                                                                   4-(3-chloro-1,4-dihydro-1,4-dioxo-2-naphthalenyl)-                                                    182-183                                               1-piperazinecarboxaldehyde                                    14 2-methylpiperazine                                                                         2-chloro-3-(3-methyl-1-piperazinyl)-1,4-naphtha-                                                      134-136                                               lenedione                                                     15  .sub.--N--benzylpiperazine                                                                2-chloro-3-[4-(phenylmethyl)-1-piperazinyl]-1,4-                                                      117-119                                               napthalenedione, hydrochloride                                16 piperazinecarboxylic acid                                                                  4-(3-chloro-1,4-dihydro-1,4-dioxo-2-naphthalenyl)-                                                    107-108                                  ethyl ester  1-piperazinecarboxylic acid, ethyl ester, hydro-                              chloride                                                      17  .sub.--N--(2-benzothiazolyl)-1-                                                           2-[4-(2-benzothiazolyl)-1-piperazinyl]-3-chloro-                                                      141-146                                  piperazine   1,4-naphthalendione, hydrochloride                            18  .sub.--N--(6-chloro-3-pyridazin-                                                          2-chloro-3-[4-(6-chloro-3-pyridazinyl)-1-pipera-                                                      140-142                                  yl)-1-piperazine                                                                           zinyl]-1,4-naphthalenedione, hydrochloride                    19  .sub.--N--[2-(3-bromophenyl)-4-                                                           2-[4-[2-(3-bromophenyl)-4-pyrimidinyl]-1-pipera-                                                      185-187                                  pyrimidinyl]-1-piperazine                                                                  zinyl]-3-chloro-1,4-naphthalenedione                          __________________________________________________________________________

Example 20N-[1,4-Dihydro-1,4-dioxo-3-[4-(phenylmethyl)-1-piperazinyl]-2-naphthalenyl]acetamide

A mixture of 500 mg of 2-acetylamino-3chloro-1,4-naphthoquinone, 800 mgof N-benzylpiperazine and 40 ml of absolute ethanol was heated at refluxfor 3 hours, then the solvent was removed. The remainder was passedthrough a small plug of silica gel and eluted with chloroform. Theeluate was concentrated to a solid which was recrystallized fromdichloromethane/hexane, giving 700 mg of the desired product, mp153°-155° C.

Following the procedure of Example 20, using appropriate amine startingmaterials and 2-acetylamino-3-chloro-1,4-naphthoquinone, the products ofExamples 21-28, listed in Table V were obtained.

                                      TABLE V                                     __________________________________________________________________________    Ex.                                                                              Amine        Product                 MP °C.                         __________________________________________________________________________    21  .sub.--N--[2-(4-morpholinyl)-2-                                                            .sub.--N--[1,4-dihydro-3-[4-[2-(4-morpholinyl)-2-oxo-                                                190-200                                  oxoethyl]-1-piperazine                                                                     ethyl]-1-piperazinyl]-1,4-dioxo-2-napthalenyl]-                               acetamide                                                     22  .sub.--N--(2-oxo-2-(1-pyrrolidin-                                                          .sub.--N--[1,4-dihydro-1,4-dioxo-3-[4-[2-oxo-2-(1-pyrroli                    -                       130-160                                  yl)ethyl]-1-piperazine                                                                     dinyl)ethyl]-1-piperazinyl]-2-naphthalenyl]-                                                          (dec.)                                                acetamide                                                     23  .sub.--N--(2-benzothiazolyl)-1-                                                            .sub.--N--[3-[4-(2-benzothiazolyl)-1-piperazinyl]-1,4-                                               145-150                                  piperazine   dihydro-1,4-dioxo-2-naphthalenyl]acetamide                    24 piperazinecarboxylic acid                                                                  4-[3-(acetylamino)-1,4-dihydro-1,4-dioxo-2-naph-                                                      200-202                                  ethyl ester  thalenyl]-1-piperazinecarboxylic acid, ethyl ester            25  .sub.--N--(1,3-benzodioxol-5-yl-                                                           .sub.--N--[3-[4-(1,3-benzodioxol-5-ylmethyl)-1-pipera-                                               199-201                                  methyl)piperazine                                                                          zinyl]-1,4-dihydro-1,4-dioxo-2-naphthalenyl]-                                 acetamide                                                     26  .sub.--N--(2-pyridinyl)piperazine                                                          .sub.--N--[1,4-dihydro-1,4-dioxo-3-[4-(2-pyridinyl)-1-                                               167-169                                               piperazinyl]-2-naphthalenyl]acetamide                         27  .sub.--N--(4-fluorophenyl)pipera-                                                          .sub.--N--[3-[4-(4-fluorophenyl)-1-piperazinyl]-1,4-                                                 185-186                                  zine         dihydro-1,4-dioxo-2-naphthalenyl]acetamide                    28  .sub.--N--[3-(trifluoromethyl)-                                                            .sub.--N--[1,4-dihydro-1,4-dioxo-3-[4-[3-(trifluormeth-                                              168- 170                                 phenyl]piperazine                                                                          yl)phenyl]-1-piperazinyl]-2-naphthalenyl]acetamide            __________________________________________________________________________

Example 29 4-(3-Chloro-1,4-dihydro-1,4-dioxo-2-naphthalenyl)-N-(2-chlorophenyl)-1-piperazinecarboxamide

A 2.76 g portion of 3-chloro-2piperazine-1, 4-naphthoquinone wasdissolved in 75 ml of chloroform. To this was added dropwise a solutionof 2-chlorophenyl isocyanate in ether. This mixture was stirred for 2hours and then evaporated. The residue was triturated in ether, giving2.3 g of the desired product, mp 160°-163° C.

Following the procedure of Example 29, using appropriate isocyanatestarting materials and 3-chloro-2-piperazine-1,4-naphthoquinone, theproducts of Examples 30-32, listed in Table VI were obtained.

                                      TABLE VI                                    __________________________________________________________________________    Ex.                                                                              Isocyanate   Product                 MP °C.                         __________________________________________________________________________    30 2-fluorophenyl isocyanate                                                                  4-(3-chloro-1,4-dihydro-1,4-dioxo-2-naphthalenyl)-                                                    >120                                                   .sub.--N--(2-fluorphenyl)-1-piperazinecarboxamide                                                    (dec.)                                31 3-(trifluoromethyl)phenyl                                                                  4-(3-chloro-1,4-dihydro-1,4-dioxo-2-naphthalenyl)-                                                    >150                                     isocyanate    .sub.--N--[3-(trifluoromethyl)phenyl]-1-piperazinecar-                                               (dec.)                                                boxamide                                                      32 4-chlorophenyl isocyanate                                                                  4-(3-chloro-1,4-dihydro-1,4-dioxo-2-naphthalenyl)-                                                    oil                                                    .sub.--N--(4-chlorophenyl)-1-piperazinecarboxamide           __________________________________________________________________________

Example 33 4-(3-Chloro-1,4-dihydro-1,4-naphthalenyl)-1-piperazinecarboxylic acid, 2-methylpropyl ester

A solution of 830 mg of 3-chloro-2-piperazinyl-1,4-naphthoquinone in 50ml of tetrahydrofuran was added dropwise to a solution of 0.39 ml ofbutyl chloroformate in 10 ml of tetrahydrofuran. This mixture wasstirred for 20 minutes, then filtered and the filtrate concentrated toan oil. The oil was crystallized from ether/hexane, giving 360 mg of thedesired product, mp 92°-94° C.

Following the procedure of Example 33, using appropriate carbonylchloride starting materials and3-chloro-2-piperazinyl-1,4-naphthoquinone, the products of Examples34-40, listed in Table VII were obtained.

                                      TABLE VII                                   __________________________________________________________________________    Ex.                                                                              Carbonyl chloride                                                                          Product                 MP °C.                         __________________________________________________________________________    34 2-chlorobenzoyl chloride                                                                   1-(2-chlorobenzoyl)-4-(3-chloro-1,4-dihydro-1,4-                                                       97-101                                               dioxo-2-naphthalenyl)piperazine                               35 4-butylbenzoyl chloride                                                                    1-(4-butylbenzoyl)-4-(3-chloro-1,4-dihydro-1,4-                                                       oil                                                   dioxo-2-naphthalenyl)piperazine                               36 benzylchloroformate                                                                        4-(3-chloro-1,4-dihydro-1,4-dioxo-2-naphthalenyl)-                                                    oil                                                   1-piperazinecarboxylic acid, phenylmethyl ester               37 trichloroethylchlorofor-                                                                   4-(3-chloro-1,4-dihydro-1,4-dioxo-2-naphthalenyl)-                                                    oil                                      mate         1-piperazinecarboxylic acid, 2,2,2-trichloroethyl                             ester                                                         38 acetyl chloride                                                                            1-acetyl-4-(3-chloro-1,4-dihydro-1,4-dioxo-2-                                                         135-136                                               naphthalenyl)piperazine                                       39 oleyl chloride                                                                             1-(3-chloro-1,4-dihydro-1,4-dioxo-2-naphthalenyl)-                                                    semi-                                                 4-(1-oxo-9-octadecenyl)piperazine                                                                     solid                                 40 dimethylaminocarbonyl                                                                      4-(3-chloro-1,4-dihydro-1,4-dioxo-2-naphthalenyl)-                                                    113-115                                  chloride      .sub.--N, .sub.--N--dimethyl-1-piperazinecarboxamide         __________________________________________________________________________

Example 41 4-(1,4-Dihydro-3-methyl-1,4-dioxo-2-naphthalenyl)-1-piperazinecarboxylic acid, ethyl ester

A mixture of 1.88 g of 2,3-epoxy-3-methyl-1, 4-naphthoquinone, 3.16 g ofpiperazinecarboxylic acid, ethyl ester and 100 ml of absolute ethanolwas stirred for 12 hours at 50° C. The solvent was then removed and theremainder filtered through a one inch plug of silica gel and eluted withchloroform. The eluate was evpaorated, giving 1 g of the desired productas a viscous red oil.

Following the procedure of Example 41, using appropriate amine startingmaterials and 2,3-epoxy-3methyl-1,4-naphthoquinone, the products ofExamples 42-51, listed in Table VIII were obtained.

                                      TABLE VIII                                  __________________________________________________________________________    Ex.                                                                              Amine         Product                 MP °C.                        __________________________________________________________________________    42  .sub.--N--(2-benzothiazolyl)-1-                                                            2-[4-(2-benzothiazolyl)-1-piperazinyl]-3-methyl-                                                      100-150                                 piperazine    1,4-naphthalenedione    (dec.)                               43  .sub.--N--benzylpiperazine                                                                 2-methyl-3-[4-(phenylmethyl)-1-piperazinyl]-1,4-                                                      101-103                                               naphthalenedione                                             44  .sub.--N--(2-pyridinyl)piperazine                                                          2-methyl-3-[4-(2-pyridinyl)-1-piperazinyl]-1,4-                                                       87-92                                                 naphthalenedione                                             45  .sub.--N--[3-(trifluoromethyl)-                                                            2-methyl-3-[4-[3-(trifluoromethyl)phenyl]-1-                                                          109-110                                 phenyl]piperazine                                                                           piperazinyl]-1,4-naphthalenedione                            46  .sub.--N--acetylmorpholino                                                                 4-[[4-(1,4-dihydro-3-methyl-1,4-dioxo-2-naphtha-                                                      semi-                                   piperazine    lenyl)-1-piperazinyl]acetyl]morpholine                                                                solid                                47  .sub.--N--acetylpyrrolidino                                                                1-[[4-(1,4-dihydro-3-methyl-1,4-dioxo-2-naphtha-                                                      semi-                                   piperazine    lenyl)-1-piperazinyl]acetyl]pyrrolidine                                                               solid                                48 piperazinecarboxaldehyde                                                                    4-(1,4-dihydro-3-methyl-1,4-dioxo-2-naphthalenyl)-                                                    143-145                                               1-piperazinecarboxaldehyde                                   49  .sub.--N--(4-fluorophenyl)pipera-                                                          2-[4-(4-fluorophenyl)-1-piperazinyl]-3-methyl-1,4-                                                    120-121                                 zine          naphthalenedione                                             50  .sub.--N--(1,3-benzodioxol-5-yl-                                                           2-[4-(1,3-benzodioxol-5-ylmethyl)-1-piperazinyl]-                                                     90-91                                   methyl)piperazine                                                          3-methyl-1,4-naphthalenedione                                                 51  .sub.--N--phenylpiperazine                                                                 2-methyl-3-(4-phenyl-1-piperazinyl)-1,4-naphtha-                                                      59-61                                                 lenedione                                                    __________________________________________________________________________

Example 52 2-[4-(2-Benzothiazolyl)hexahydro-1H-diazepin-1-yl]b3-chloro-1,4-naphthalenedione

A 2.33 g portion of N-(2-benzothiazolyl) hexahydro-1H-1,4-diazepin-1-ylwas dissolvedom 25 of absolute ethanol and 1.13 g of 2,3-dichloro-1,4-naphthoquinone was added. This mixture was heated at reflux for 4hours, then cooled to room temperature and the solvent removed. Theremainder was filtered through a plug of silica gel and then eluted withchloroform followed by 5% methanol in chloroform. The eluate wasconcentrated to a solid which was triturated with ether, giving 400 mgof the desired product as a glass.

Example 53N-[3-[4-(2-Benzothiazolyl)hexahydro-1H-diazepin-1-yl]-1,4-dihydro-1,4-dioxo-2-naphthalenyl]acetamide

The procedure of Example 52 was repeated, using 466 mg ofN-(2-benzothiazolyl)hexahydro-1H-1, 4diazepin-1yl and 500 mg of2acetylamino-3-chloro-1, 4-naphthoquinone, giving 400 mg of the desiredproduct as a glass.

Example 54 N-(4-Chlorophenyl)-4-(1,4-dihydro-3-methyl-1,4-dioxo-2naphthalenyl)-1-piperazinecarboxamide

A solution of 150 mg of 3-methyl-2piperazinyl-1,4-naphthoquinone in 50ml of tetrahydrofuran was treated with a solution of 100 mg of4-chlorophenylisocyanate in 10 ml of tetrahydrofuran. This mixture wasstirred 1/2 hour, then evaporated in vacuo and the residue taken up indichloromethane and filtered. The filtrate was evaporated and theresidue recrystallized from dichloromethane/hexane, giving 200 mg of thedesired product, mp 190°-192° C.

Example 552-[4-(2-Benzoxazolyl)-1-piperazinyl]-3-chloro-1,4-naphthalenedione

A solution of 1.0 g of N-(2-benzoxazolyl)-1piperazine and 0.82 g ofdiazobicycloundecane in 50 ml of toluene was prepared. A 1.11 g portionof 2, 3-dichloro-1,4-naphthoquinone was added and the mixture wasstirred for 12 hours and then evaporated. The residue was taken up indichloromethane, filtered and the filtrate evaporated, giving 1.43 g ofthe desired product, mp 192°-193° C.

Example 561-(3-chloro-1,4-dihydro-1,4-dioxo-2-naphthalenyl)-4-[(2-chlorophenyl)sulfonyl]piperazine

A solution of 1.0 g of 3-chloro-2-piperazinyl-1,4-naphthoquinone in 20ml of pyridine was prepared. To this was added 750 mg of2-chlorobenzenesulfonyl chloride. The mixture was stirred for 10minutes, then heated on a steam bath for 2 hours, then diluted withwater and extracted with three 50 ml portions of dichloromethane. Theextracts were combined, washed with water, dried and evaporated invacuo. The residue was chromatographed on silica gel, eluting with 2%methanol in chloroform. The active fraction was evaporated in vacuo,giving 830 mg of the desired product, mp 176°-177° C.

Example 571-(3-Chloro-1,4-dihydro-1,4-dioxo-2-naphthalenyl)-4-[[2-(trifluoromethyl)phenyl]sulfonyl]piperazine

A 1.5 g portion of 3-chloro-2-piperazinyl-1,4-naphthoquinone and 1.26 gof 2-trifluoromethylbenzenesulfonyl chloride were reacted as describedin Example 56, giving 1.53 g of the desired product, mp 122°-124° C.

Example 584-(3-Chloro-1,4-dihydro-1,4-dioxo-2-naphthalenyl)-N-(3-chlorophenyl)-2-methyl-1-piperazinecarboxamide

A solution of 1.0 g of2-chloro-3-(3-methyl-1piperazinyl)-1,4-naphthalenedione in 300 ml ofether was prepared. A solution of 530 mg of 3-chlorophenyl isocyanate in25 ml of ether was added, the mixture was stirred for 1/2 hour, thenevaporated in vacuo. The residue was dissolved in dichloromethane,filtered and the filtrate evaporated, giving 950 mg of the desiredproduct, mp 112°-114° C.

Example 59N-Acetyl-N-[3-[4-(4-fluorophenyl)-1-piperazinyl]-1,4-dihydro-1,4-dioxo-2-naphthalenyl]acetamide

A mixture of 1.66 g of 2-[N,N-diacetylamino]-3-chloro-1,4-naphthoquinoneand 1.441 g of 1-(4-fluorophenyl)-piperazine in 50 ml of ethanol wasrefluxed overnight, then evaporated in vacuo. The residue was dissolvedin dichloromethane, filtered through silica gel and eluted withchloroform:methanol (100:2). The eluent was evaporated and the residuecrystallized from dichloromethane/-hexane, giving 800 ml of the desiredproduct, mp 149°-150° C.

Example 60N-Acetyl-N-[1,4-dihydro-1,4-dioxo-3-[4-[(1,2,3,6-tetrahydro-2,6-dioxo-4-pyrimidinyl)methyl]-1-piperazinyl]-2-naphthalenyl]acetamide

A 1.166 g portion of 2-[N,N-diacetylamino]-3-chloro-1,4-naphthoquinoneand 1.681 g of 6-methyluracil-1-piperazine were reacted as described inExample 59, giving 960 mg of the desired product, mp 152°-154° C.

Example 61 2-Hydroxy-3-[4-[3-(trifluoromethyl)phenyl]-1-piperazinyl]-1,4-naphthalenedione

A mixture of 1.74 g of 2,3-epoxy-2,3-dihydro-1,4-naphthoquinone and 2.30g of N-[3-(trifluoromethyl) phenyl]-piperazine in 100 ml of absoluteethanol was stirred for 20 hours, then evaporated. The residue wasdissolved in dichloromethane, filtered through hydrous magnesiumsilicate and then chromatographed on silica gel, eluting withhexane:ethyl acetate (4:1), giving 1.2 g of the desired product, mp167°-169° C.

Example 62 2-Hydroxy-3-[methyl[2-[methyl(phenylmethyl)amino]-ethyl]amino]-1,4-naphthalenedione

A mixture of 2.61 g of 2,3-epoxy-2, 3-dihydro-1,4-naphthoquinone, 2.67 gof N-benzyl-N,N'-dimethylethylene-diamine and 150 ml of absolute ethanolwas stirred for 20 hours, then concentrated to one-half its originalvolume and refrigerated overnight. The solvent was removed, the residuedissolved in dichloromethane and passed through a pad of hydrousmagnesium silicate and silica, eluting first with dichloromethane, thenwith 1% methanol in dichloromethane. The active fraction was flashchromatographed eluting with dichloromethane followed by 2% methanol indichloromethane. The active fraction was evaporated and the residuetriturated in dichloromethane/-hexane giving 900 mg of the desiredproduct, mp 121°-123° C.

Example 634-(1,4-Dihydro-3-hydroxy-1,4-dioxo-2-naphthalenyl)-1-piperazinecarboxaldehyde

A mixture of 3.48 g of 2,3-epoxy-2,3-dihydro-1,4-naphthoquinone, 2.28 of1-piperazinecarboxaldehyde and 200 ml of absolute ethanol was stirredfor 20 hours, then concentrated to one-half its original volume andrefrigerated overnight. The solid was collected and recrystallized fromdichloromethane/ethanol, giving 2.65 g of the desired product, mp200°-203° C.

Example 642-[4-(2-Benzoxazolyl)-1-piperazinyl]-3-hydroxy-1,4-naphthalenedione

A mixture of 3.48 g of 2,3-epoxy-2, 3-dihydro-1,4-naphthoquinone, 2.03 gof 2-(1-piperazinyl)benzoxazole and 200 ml of absolute ethanol wasstirred for 18 hours and then filtered. The filtrate was concentrated todryness and the residue flash chromatographed, eluting withdichloromethane, then 1% methanol in dichloromethane. The desiredfraction was evaporated, then recrystallized twice fromdichloromethane/ethanol, giving 533 mg of the desired product, mp 190°C. (dec.).

Example 654-(1,4-Dihydro-3-hydroxy-1,4-dioxo-2-naphthalenyl)-1-piperazinecarboxylicacid, ethyl ester

A mixture of 1.174 g of 2,3-epoxy-2, 3-dihydro-1,4-naphthoquinone, 1.58g of ethyl-N-piperazinocarboxylate and 100 ml of absolute ethanol wasstirred for 24 hours, then evaporated. The residue was chromatographedon silica gel, eluting with 5% methanol in chloroform, giving 1.0 g ofthe desired product, mp 115°-118° C.

Example 662-[4-[2-(3-Bromophenyl)-4-pyrimidinyl]-1-piperazinyl]-3-methyl-1,4-naphthalenedione

A mixture of 940 mg of 2,3-epoxy-2-methyl-1,4-naphthoquinone, 1.59 g of3-bromophenyl-4-pyrimidinyl-1-piperazine and absolute ethanol wasstirred for 48 hours. The solid was collected, washed with absoluteethanol and dried, giving 500 mg of the desired product, mp 120° C.(dec.).

We claim:
 1. A compound selected from the group consisting of those ofthe formula: ##STR8## wherein R₁ is selected from the group consistingof halogen, hydroxy, alkyl(C₁ -C₄), alkoxy(C₁ -C₃),--NHCOCH₃ and--N(CICG₃)₂ ; R₂ is seleccted from the group hydrogen and alkyl(C₁ -C₄);R₃ and R₄ are individually alkyl(C₁ -C₃); R₅ is selected from the groupconsisting of hydrogen, formyl, acetyl, --COOalkyl(C₁ -C₄), --COOCH₂C(halogen)₃, --CO(CH₂)₇ CH═CH(CH₂)₇ CH₃, --CON[alkyl(C₁ --C₃)]₂, phenyl,benzyl, 2-, 3- or 4-halobenzoyl, 2-,3-or 4-alkyl(C₁ -C₆)benzoyl,monosubstituted phenyl (wherein the substituents may be ortho, meta orpara and are halogen or trifluoromethyl), monosubstituted phenylcarboxamide (wherein the substituents may be meta or para and arehalogen or trifluoromethyl) and moieties of the formulae: ##STR9## thepharmacologically acceptable acid-addition salts thereof.
 2. Thecompound according to claim 1;2-chloro-3-[methyl[2-[methyl(phenylmethyl)amino]ethyl]amino]-1,4-naphthalenedione.3. The compound according to claim 1;2-hydroxy-3-[methyl]2-[methyl(phenylmethyl)amino]ethyl]amino]-1,4-naphthalenedione.4. A method of treating asthma and allergic diseases in a warm-bloodedanimal which comprises administering to said animal an effective amountof a compound of claim
 1. 5. A method of treating inflammation in awarm-blooded animal which comprises administering to said animal aneffective amount of a compound of claim
 1. 6. A composition of matter indosage unit form comprising from about 5 mg to about 1500 mg of acompound of claim 1.